OVERVIEW: What every practitioner needs to know

Are you sure your patient has malaria? What are the typical findings for this disease?

Malaria must be considered in the differential diagnosis of a febrile illness in a patient who has returned from travel in a malaria-endemic country. Fevers due to Plasmodium falciparum, the most common and virulent species of malaria, usually begin approximately 1 to 2 weeks after the bite of an infected mosquito. Natural immunity and the use of antimalarial prophylaxis may prolong the incubation period. Relapsing malaria due to Plasmodium vivax or ovale can occur weeks, months or even years after the initial infection.

Malaria usually presents with fever without any localizing signs or symptoms. If the disease is uncomplicated, it is often associated with other non-specific constitutional symptoms such as chills, headache, myalgia and malaise. Gastrointestinal complaints are also common in children. The symptoms often occur intermittently as a result of the parasite reproductive life cycle within the erythrocytes. Common physical findings include jaundice, hepatosplenomagaly and pallor. Evidence of cerebral involvement or other end organ damage indicates severe disease that can be rapidly life-threatening.

Does your patient have signs or symptoms of severe disease?

Malaria fatalities are associated with specific manifestations of severe disease. It is critical to distinguish uncomplicated disease from severe malaria that requires emergent, parenteral therapy. Among children who live in malaria-endemic countries, cerebral malaria (impaired consciousness or seizures without another cause) and severe anemia are the most common presentations of severe disease. In travelers who have no pre-existing malaria immunity, other forms of end organ damage occur including renal failure, acute respiratory distress syndrome, disseminated intravascular coagulopathy, metabolic acidosis, shock and hemoglobinuria.

Patients with a high parasite burden of greater than or equal to 5% of erthyrocytes infected with malaria are also at risk for severe and life threatening complications.

What other disease/condition shares some of these symptoms?

For the pediatrician evaluating a febrile child who is also a returned traveler, the differential diagnosis must include both domestically acquired illnesses that may be of infectious or non-infectious origin and also conditions that could have resulted from unique exposures during international travel.

Other systemic febrile illnesses that are rare in the United States and Europe and are usually travel-associated include the following:

Typhoid fever

Meningococcal infection

Dengue fever

Rickettsial infection

Leptospirosis

Acute schistosomiasis (Katayama fever)

Amebic liver abscess.

These can be considered in the differential diagnosis in the febrile returned traveler, but malaria should remain at the top of the list until it is definitively excluded.

Children with anemia who are from or who have travelled to malaria-endemic countries should be tested for malaria prior to the administration of iron replacement therapy. Malarial anemia is not due to iron deficiency and high concentration of free iron may exacerbate malaria infection.

What caused this disease to develop at this time?

Five species of Plasmodium have been identified as causing disease in humans. They are definitively distinguished by microscopy in clinical practice and by polymerase chain reaction in a research setting, but the location of the exposure can provide important diagnostic clues.

P. falciparum is associated with most severe disease. It is transmitted in all locations where malaria can be found, but it is the most commonly infecting species in sub-Saharan Africa.

P. vivax is the second most common infecting species in the world and outside of Africa it is often the most frequent form of malaria. It is found in Asia and Central and South America. It is rarely found in Africa. P. ovale infection is rare and found predominantly in Africa. P. vivax and ovale can cause relapsing disease due to the persistence of hypnozoites, dormant states of the parasites in the liver. Only treatment with primaquine can eliminate hypnozoites.

P. malariae is found in most malaria-endemic areas and causes mild, persistent infection. Although it does not have a dormant liver phase, it can cause a prolonged, chronic infection.

P. knowlesi is a species that typically infects macaques. It was recently identified as a cause of human disease throughout Southeast Asia. Morphologically, it is indistinguishable from P. malariae infection. Unlike that mild form of disease, P. knowlesi can cause complicated and fatal infection.

In reviews of imported cases of malaria, the individuals at highest risk for presenting with malaria are those who took no or inappropriate malaria prophylaxis and/or individuals who traveled to visit friends and relatives (compared to standard tourists and business travelers).

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

A malaria smear or a rapid diagnostic test should be done urgently whenever malaria is suspected. The traditional gold standard for the diagnosis is a thick and thin blood smear. Thick smears are more sensitive than thin smears; parasite densities as low as 5-10 parasites per microliter of blood can be detected. Thin smears, which are stained to keep the morphology of the red blood cells intact, are useful for quantitating high parasitemia and for identifying the specific parasite species.

Rapid diagnostic tests for malaria that utilize immunochromatography to detect parasite enzymes and/or antigens have been developed. BinaxNOW Malaria (Binax, Inc., Inversness Medical Professional Diagnostics) is the only U.S. FDA-approved rapid diagnostic test. It detects aldolase which is found in all four human Plasmodium species and histidine-rich protein-2 , an antigen that is unique to P. falciparum. When used in hospitals in the United States, rapid diagnostic tests are more sensitive than thick smears for the detection of parasitemia, when polymerase chain reaction DNA detection is used as the gold standard. Sensitivity is lower for detecting non-falciparum and mixed infections compared to P. falciparum mono-infection. False positive rapid tests can occur following treatment of a recent malaria infection.

Would imaging studies be helpful? If so, which ones?

No imaging is required for the diagnosis of malaria, although targeted studes to assess localized symptoms may be warranted to rule out concomitant illnesses (e.g., chest radiograph for pneumonia).

Confirming the diagnosis

If malaria infection is suspected, a rapid diagnostic test, if it is available, and a malaria smear should be done simultaneously. If the rapid test or malaria smear is positive, treatment should be initiated immediately. Ideally, the diagnosis based on a rapid test should be confirmed by microscopy, as well. Microscopy is necessary to determine infecting species of the infection and quantify the the parasitemia for severity classification and to monitor response to therapy.

A single negative malaria smear makes the diagnosis of malaria unlikely, but not impossible. Parasites may be present below the level of detection by microscopy in the blood because the majority are sequestered in the small capillary beds. If malaria is still suspected after one negative result, malaria smears can be repeated every 12-24 hours up to two additional times to rule out infection.

The role of repeated rapid diagnostic tests after an initial negative test when the clinical suspicion is high has not been evaluated.

If you are able to confirm that the patient has malaria, what treatment should be initiated?

For patients with uncomplicated disease, treatment should be initiated as soon as the diagnosis is confirmed. See Table I for FDA-approved available treatment options for malaria.

Malaria treatment options and pediatric dosages

Patients should not be treated with the same medication that they used for prophylaxis because of the concern that the infecting parasites may be resistant. The CDC recommends that all patients with malaria be admitted to the hospital for observation for the first 24 hours to ensure they can tolerate the oral medication and that the clinical and parasitological status improve.

Patients with suspected complicated malaria may require the initiation of therapy even before the diagnosis is confirmed because any delay in treatment may lead to poor outcomes.

In malaria-endemic countries, quinine is used for the parenteral treatment of malaria. In the United States, quinidine has been available in hospital pharmacies because of its use as an anti-arrhythmic agent. However, its use for cardiac purposes has been mostly abandoned and as a result many hospitals do not have immediate access to the emergency treatment of severe malaria. If quinidine is required on an emergency basis, Eli Lilly has a program to provide the medication. Veteran Administration hospitals have rapid access to quinidine and could be contacted if it is not available at the treating hospital. Quinidine is administered with doxycycline, tetracycline or clindamycin (for children under 8 years of age).

Intravenous artesunate is superior to quinine for the treatment of severe disease because it decreases the parasite burden more rapidly. At this time, it is available from the CDC through an investigational protocol. It is stored in several locations throughout the country so it can be shipped to most locations within hours.

For patients with severe disease, without any pre-existing contraindications, whichever drug is available first should be administered. For patients with cardiac conduction abnormalities or who develop signs of cardiac toxicity on quinidine, intravenous artesunate should be used. After the patient has clinically stabilized and can tolerate oral medication, a complete course of oral therapy should be prescribed.

The role of exchange transfusion in cases of hyperparasitemia (>5-10%) is controversial but generally recommended for adults. It has not been studied in children.

In addition to antimalarial therapy, supportive therapy is essential. Hypoglycemia is common. Glucose levels should be checked and corrected as soon as the patient can be evaluated and should be monitored on a regular basis. Fluid resuscitation should be given to correct any deficits but should be used cautiously to prevent exacerbation of cerebral edema, which is common in cerebral malaria.

Seizures may require anti-epileptic medication, but may also be a result of metabolic disturbances, especially hypoglycemia. Transfusion may be required if the anemia is severe and symptomatic. Broad spectrum antibiotics are often administered after obtaining blood cultures and lumbar puncture, if clinically indicated. Bacteremia can occur in association with malaria infection.

When P. vivax or ovale are diagnosed by microscopy, primaquine must be administered as terminal prophylaxis after the blood stage infection has been cured, to eliminate the hypnozoites that are latent in the liver. None of the treatments for the blood stage infection have documented activity against this stage of infection. Primaquine can cause a hemolytic crisis in people with G6PD deficiency, so G6PD activity levels should be measured prior to administration of primaquine.

What are the adverse effects associated with each treatment option?

Quinidine is administered as a loading dose followed by a continuous intravenous infusion. Because of its cadiotoxicity, it must be given in an intensive care setting with continuous cardiac monitoring. The most worrisome severe toxicity most commonly noted is prolonged QT interval, increasing the risk for a fatal arrhythmia. Quinine and quinidine induce a state of hyperinsulinemia which can cause or worsen hypoglycemia. These medications also cause cichonism, a constellation of symptoms including headache, tinnitus, visual disturbance and vertigo, that are commonly associated with the administration of these derivatives of the South American Cinchona tree bark.

Among the oral therapies, quinine is the most poorly tolerated due to cichonism, followed by mefloquine. At treatment dosage, mefloquine is frequently associated with neuro-psychiatric side effects that interfere with compliance.

Chloroquine can cause gastro-intestinal upset and headache. Pruritis is common among Africans and it not typically responsive to antihistamines.

Adverse reactions to atovaquone-proguanil and lumefantrine-artemether are rare and mild. For atovaquone-proguanil, gastro-intestinal symptoms and pruritis have been reported and for artemether-lumefantrine, palpitations and dizziness can occur.

What are the possible outcomes of malaria?

Malaria deaths are rare in the United States. Occasional fatalities occur as a result of delayed diagnosis in patients with travel-related exposures who did not receive evaluation for malaria early in the course of the illness.

Once antimalarial medication has been initiated, the malaria smears should be obtained one to two times per day to document resolution of the infection. For treatment with quinine or quinidine, it is not unusual for the parasitemia to increase in the first 12-24 hours, before the drug has had its maximal effect.

What causes this disease and how frequent is it?

Malaria is one of the leading causes of death among children in developing countries. It is estimated to be responsible for nearly one million deaths per year, most of those among children in sub-Saharan Africa. Young children are most susceptible to the disease in Africa because they have not yet acquired a state of partial immunity. In contrast, adults and children who travel or who live in low transmission settings such as Southeast Asia and South America, are susceptible to disease regardless of age.

Malaria is transmitted through the bite of an infected female anopheles mosquito. The mosquito injects sporozoites into the blood stream and the sporozoites rapidly enter the liver where they undergo replication within the hepatocytes for 1 to 2 weeks, during which time patients are asymptomatic.

After the hepatic phase, merozoites are released into the peripheral circulation, where they infect and replicate in erythrocytes. This blood stage of infection causes symptomatic disease. The merozoites continue to replicate, rupture and invade new red blood cells until the host immune response and/or therapy eliminate the infection. Some merozoites differentiate into gametocytes, the form of the malaria parasite that is transmissible to the mosquito.

When a female mosquito takes a blood meal from an infected patient, the gametocytes undergo sexual reproduction in her midgut and eventually develop into sporozoites and migrate to the salivary gland where transmission can be perpetuated with the next human bite.

Infection in the absence of travel to a malaria-endemic country is extremely rare. Infants born to mothers with active malaria infection may acquire congenital malaria infection via maternal-fetal transfusion. Cases have been reported due to blood transfusion and transplantation. In addition, domestic transmission can occur when malaria-infected visitors come into conact with Anopheles mosquitoes, which are still found in the United States.

How do these pathogens/genes/exposures cause the disease?

All forms of malaria cause fever through the release of merozoites into the circulation, leading to a host inflammatory response. Anemia is a result of destruction of infected and also uninfected erythrocytes as well as bone marrow suppression.

The organ damage that is responsible for severe, life threatening disease due to P. falciparum malaria is a result of the expression of proteins on the surface of infected red blood cells that cause them to adhere to capillaries in organ beds. This phenomenon, known as sequestration, occurs in the brain, leading to cerebral malaria, as well as many other organs, even in the absence of clinical dysfunction.

Other clinical manifestations that might help with diagnosis and management

In pregnant women, parasites can sequester in the placenta, causing a chronic placental infection. This leads to maternal anemia and infant low birthweight, although it is not known if this is predominantly due to intrauterine growth restriction or prematurity. The parasites do not cross the placenta, but they do elicit an inflammatory response.

Congenital malaria infection is rare and is thought to be due to maternal-fetal transfusion, rather than transplacental infection. Infants born to mothers with active or recent malaria infection should be tested for malaria because infection can be asymptomatic or minimally symptomatic in newborns.

What complications might you expect from the disease or treatment of the disease?

In the United States, the case fatality rate for malaria among hospitalized is approximately 1% or less. Deaths almost always occur in cases when the diagnosis or appropriate treatment was delayed. Patients who experience uncomplicated disease and are successfully treated do not experience sequelae. In contrast, children who survive cerebral malaria may have long term neurological disabilities.

Are additional laboratory studies available; even some that are not widely available?

PCR is available to detect malaria infection, determine the infecting species and assess resistance to some antimalarial medications. However, these assays are not part of the clinical diagnosis of the disease.

How can malaria be prevented?

There is no vaccine available to prevent malaria. For travelers who will be in areas of malaria transmission, malaria prophylaxis, in addition to mosquito vector avoidance described below, is recommended. For children, mefloquine and atovaquone-proguanil can be used. For children over 8 years of age, doxycyline is also effective. Only atovaquone-proguanil has a pediatric formulation. For infants taking mefloquine, a pharmacist can cut the tablets into the appropriate size and place in capsules for weekly dispensing.

When traveling to malaria-endemic areas, adults and children should take precautions to avoid anopheles mosquito bites. These mosquitoes characteristically bite at dusk and night. Wearing long sleeves and long pants is a basic protective measure. Clothes can be treated with permethrin prior to travel and the insecticide maintains its activity even with washing. Personal insecticides such as DEET should be used on any exposed skin when individuals are out during the evening hours. Bed nets are recommended at night to prevent bites while sleeping. Even screened rooms often have mosquitoes present.

What is the evidence?

(This is the definitive clinical trial that demonstrated the superiority of intravenous artesunate over quinine for the treatment of severe malaria in children.)

(Surveillance data of illnesses in children after international travel, collected from travel clinics throughout the world.)

(An overview of the published literature on malaria illnesses in pediatric returned travelers.)

(Most extensive presentation of P. knowlesi, a zoonotic malaria species that has been identified causing severe disease in humans in Asia.)

Ongoing controversies regarding etiology, diagnosis, treatment

In malaria-endemic countries, artemisinin-based combination therapies are the cornerstone treatment for uncomplicated malaria. There is now evidence that artemisinin resistance is emerging in Southeast Asia. Although failure of artemisinin-based combination therapy is rare, investigators have detected prolonged parasite clearance times after initiation of therapy. Efforts are underway to better characterize artemisinin resistance and to prevent its spread to other regions.